Identifying prefrontal signatures of successful and dysfunctional attention

项目总结 注意力由几个组成部分组成，包括持续的注意、选择性的 注意力和注意力的灵活性。第一阶段，即最初的注意力集中阶段，排除了参与 其他组件使其成为我们许多更复杂行为的重要构建块。另外， 注意力障碍通常在包括但不限于精神分裂症的情况下表现为共病， 自闭症、抑郁症和癫痫，使确定治疗目标成为一个重大的公共卫生问题。 汇聚的数据表明，内侧前额叶皮质(MPFC)是支持注意转移的中枢 与其他关键结构有关，而它在最初吸引注意力方面的作用则不太清楚。不知何故，mPFC 锥体神经元整合来自多个来源的信息，代表任务规则、提示和与响应相关的信息 信息在动态活跃的集合中，并选择适当的行为反应。上一首 生理数据表明，这一惊人的计算壮举之所以成为可能，要归功于强大的调控 皮质抑制中间神经元对锥体神经元活性的影响，但许多研究缺乏监测能力 具有特异性的不同细胞类别。用纤维光度法研究mPFC中GCaMP介导的钙信号 关于小白蛋白表达的中间神经元(PVINs)，我们收集了初步数据表明PVINs 在视觉注意参与任务(AET)中，在线索知觉中扮演着新的角色。具体来说，我们有 观察到提示诱发的群体PVIN活动的增加是必要的、充分的，并且可以预测 才能成功地吸引注意力。我们假设这可能代表了一种普遍的 注意力在有注意力障碍的疾病中持续中断。然而，PVIN不会 在隔离状态下工作，mPFC锥体神经元也受到来自 丘脑内侧背侧(MD)等，以及与其他中间神经元亚型的局部回路相互作用，如 作为生长抑素(SOM)和血管活性肠多肽(VIP)表达的中间神经元，它们都有 也与认知和精神疾病功能障碍有关。不同的研究发现了不同的 涉及VIP和SST中间神经元以及SST和PV中间神经元的去抑制电路 依赖mPFC的行为。然而，调节注意力过程的精确电路主题是 在很大程度上没有特征。具体地说，特定类别中的单个中间神经元如何代表信息 在注意力分析过程中，捕捉注意力的不同成分仍有待确定。通过 K99阶段，我将接受体内钙离子成像的关键训练和注意力的设计与实现 测试我的总体假设的任务，即PVIN提供广泛的抑制来抑制分散注意力的信息 在注意投入期间，而R00阶段将检查单独的去抑制回路主题如何允许 锥体神经元集合发出信号提示和反应信息，以适当地引导分开的注意 功能。

PROJECT SUMMARY Attention is comprised of several component processes, including sustained attention, selective attention, and attentional flexibility. The first phase, the initial focusing of attention, precludes engagement of other components making it an important building block of many of our more complex behaviors. Additionally, attention impairments often present as a comorbidity in conditions including but not limited to schizophrenia, autism, depression, and epilepsy, making identifying therapeutic targets a significant public health concern. Convergent data point to the medial prefrontal cortex (mPFC) as a hub for supporting attentional shifting along with other key structures, while its role in the initial engagement of attention is less clear. Somehow, mPFC pyramidal neurons integrate information from multiple sources, represent task rules, cue, and response-related information in dynamically active ensembles, and select appropriate behavioral responses. Previous physiological data suggests this astounding computational feat is made possible due to the powerful regulation of pyramidal neuron activity by cortical inhibitory interneurons, but many studies lacked the ability to monitor distinct cell-classes with specificity. Using fiber photometry of GCaMP-mediated Ca2+ signals in mPFC parvalbumin-expressing interneurons (PVINs), we have collected preliminary data demonstrating that PVINs play a novel role in cue-perception during a visual attentional engagement task (AET). Specifically, we have observed that cue-evoked population increases in PVIN activity are necessary, sufficient, and can be predictive for successful attentional engagement. We hypothesize that this may represent a universal mechanism of attention that is consistently disrupted across diseases with attentional impairments. PVINs however, do not operate in isolation, and mPFC pyramidal neurons are also regulated by long-range inputs from the mediodorsal thalamus (MD) among others, and local circuit interactions with other interneuron subtypes, such as somatostatin (SOM) and vasoactive intestinal polypeptide (VIP) expressing interneurons, all of which have also been linked to cognition and psychiatric disease dysfunction. Separate studies have identified distinct disinhibitory circuits involving VIP and SST interneurons, and SST and PV interneurons that can regulate mPFC-dependent behaviors. However, the precise circuit motifs which regulate attentional processes are largely uncharacterized. Specifically, how individual interneurons in specific classes represent information during attentional assays capturing distinct components of attention remains to be determined. Through the K99 phase, I will receive critical training in in vivo Ca2+ imaging and design and implementation of attentional tasks to test my overall hypothesis that PVINs provide broad inhibition to suppress distracting information during attentional engagement, while the R00 phase will examine how separate disinhibitory circuit motifs allow pyramidal neuron ensembles to signal cue and response information to appropriately guide separate attention functions.